Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0152030 (skin irritation)
 2,146 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The metabolism and mutagenic activity of 4-fluorobenzo[j]fluoranthene (4F-B[j]F) and 10-fluorobenzo[j]fluoranthene (10F-B[j]F) were evaluated and compared with benzo[j]fluoranthene (B[j]F) using an identical rat liver homogenate preparation. Previous studies have shown that the major genotoxic metabolites of B[j]F are the 4,5- and 9,10-dihydrodiol. The 9,10-dihydrodiol was the principal metabolite formed in the case of 4F-B[j]F, while the 4,5-dihydrodiol was the principal metabolite formed in the metabolism of 10F-B[j]F. Studies on the relative genotoxicity of these fluorinated derivatives were performed to indirectly determine the possible contribution of the 4,5- and 9,10-dihydrodiol in the activation of B[j]F to a genotoxic agent. In the presence of microsomal activation, both of these fluorinated derivatives of B[j]F were more mutagenic in S. typhimurium TA97a, TA98 and TA100 than B[j]F. However, differences in mutagenic potency were observed between 4F- and 10F-B[j]F. 10F-B[j]F had similar mutagenic potency to 4F-B[j]F in TA97a and TA98 at doses associated with the linear portion of the dose response curve. However, a slightly higher mutagenic response was observed with 10F-B[j]F in TA98 at doses above 5 nmol. In contrast, 4F-B[j]F was more active than 10F-B[j]F as a mutagen in TA100. The tumor-initiating activity of these analogs on mouse skin was assessed at doses of 2.0, 1.0 and 0.3 mumol. Skin irritation was observed with the fluorinated B[j]F derivatives at doses above 0.3 mumol. At a dose of 0.3 mumol, 4F-B[j]F exhibited tumorigenic activity which was similar to B[j]F. In contrast, 10F-B[j]F was less active than B[j]F at all three doses assayed. Both fluorinated derivatives of B[j]F formed higher levels of DNA adducts in vivo in mouse skin than B[j]F. A modified 32P-postlabeling method was required to detect fast migrating B[j]F:DNA adducts that went undetected in previous studies. The level of DNA adducts formed from 4F-B[j]F was considerably greater than the levels observed with 10F-B[j]F. This is consistent with the greater mutagenic activity in S. typhimurium TA100 and tumor-initiating activity exhibited by 4F-B[j]F. These studies suggest that fluorine substitution may significantly alter the intrinsic genotoxicity of the 4,5- and 9,10-dihydrodiol of B[j]F. These data also imply that B[j]F may be primarily activated via the formation of the 9,10-dihydrodiol metabolite. This pathway of activation is inconsistent with our previous studies which indicate that the 4,5-dihydrodiol is the most important pathway of activation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effect of fluorine substitution on benzo[j]fluoranthene genotoxicity. 139 15

We report a study of a series of isoquinoline derivatives, including their synthesis, in vitro microsomal leucine aminopeptidase (LAP) inhibition and antiproliferative activity on cancer cell lines. Among fourteen tested compounds, one (compound 3b) was determined to have good activity against LAP and significant antiproliferative activity against HL-60 human promyelocytic leukemia, Burkitt's lymphoma Raji, camptothecin resistant CEM/C2 leukemia cells with mutated catalytic site of topoisomerase I, its parental cell line CCRF/CEM and LoVo colon cancer. Its influence on the cell cycle was also observed. Moreover, we have confirmed that antiproliferative activity towards cancer cells is due to LAP inhibition. Docking simulation based on positioning compound 3b into the LAP active site was performed to explore the possible binding mode. The compound was able to form hydrogen bonds with Gly362 and coordinate zinc ions, which was previously suggested to be essential for inhibitory activity. Compound 3b was also characterized with a good selectivity index for cancer versus normal mammalian cells. Toxicological studies involving examination of skin sensitization, acute skin irritation/corrosion, acute dermal toxicity, acute oral toxicity and acute eye irritation/corrosion established that compound 3b is safe for use.
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PMID:Molecular docking studies, biological and toxicity evaluation of dihydroisoquinoline derivatives as potential anticancer agents. 2762 21